The biliary tract disease is a collective term for digestive diseases that occur in the gallbladder, bile duct, pancreas or pancreatic duct. A known example of the cause of occurrence of a biliary tract disease is increased biliary tract pressure due to contraction of sphincter of Oddi in the duodenal papilla, which is the furthest downstream of the biliary tract and corresponds to the distal part of the bile duct formed by confluence of the common bile duct and pancreatic duct. Known examples of the biliary tract disease caused by contraction of sphincter of Oddi include biliary obstruction, gallbladder disorder, cholelithiasis, pancreatitis, biliary dyskinesia, cholangitis and cholecystitis. Therefore, drugs that inhibit contraction of sphincter of Oddi are known to be useful as therapeutic agents for biliary tract diseases caused by contraction of sphincter of Oddi.
Further, examples of biliary tract diseases which are not caused by contraction of sphincter of Oddi, but may be exacerbated by contraction of sphincter of Oddi include primary biliary cirrhosis (which may hereinafter be referred to as “PBC”). PBC is a disease wherein interlobular bile ducts, which are bile ducts positioned upstream of the common bile duct and inside the liver, are destroyed and bile statis occurs. Obstruction of the common bile duct is known to cause exacerbation of PBC (Hastier P et al., Dig Dis Sci., 43, 2426 (1998)). Therefore, it is believed that drugs that inhibit contraction of sphincter of Oddi may ameliorate obstruction of the common bile duct and, hence, inhibit exacerbation of PBC.
Morphinan derivatives and pharmaceutically acceptable acid addition salts thereof, with their κ opioid receptor agonist activity, have been disclosed for uses as analgesics and diuretics (WO 93/015081).
They have already been disclosed for uses in antitussives (WO 95/001178), brain cell protecting agents (WO 95/003307), antipruritics (WO 98/023290), therapeutic agents for hyponatremia (WO 99/005146), ORL-1 receptor antagonists (JP 2000-53572 A), therapeutic agents for neuropathic pain (WO 01/014383), antipruritics for cornea and conjunctiva (JP 2001-163784 A), therapeutic agents for psychoneurotic disorders (WO 02/078744), therapeutic agents for drug dependence (WO 99/011289), therapeutic agents for sepsis (WO 02/089845), therapeutic agents for itching due to multiple sclerosis (WO 06/095836), therapeutic agents for schizophrenia (WO 09/001,764) and therapeutic agents for dyskinesia (WO 08/133,297). However, no therapeutic or prophylactic effect on biliary tract diseases has been disclosed.
Examples of drugs which have actions to inhibit contraction of sphincter of Oddi and are currently used as therapeutic agents for biliary tract diseases include those having actions to promote uptake of Ca2+ into intracellular Ca-store sites such as trepibutone, those having actions to inhibit binding of Ca2+ in the extracellular fluid to contractile proteins such as hymecromone, those having actions to inhibit catechol-O-methyltransferase (which may hereinafter be referred to as “COMT”), and antiserotonin actions such as flopropione, those having antimuscarinic actions such as tiquizium, those having atropine-like actions and papaverine-like actions such as oxapium, those having trypsin- and kallikrein-inhibition actions although the action mechanism for inhibition of contraction of sphincter of Oddi is unknown such as gabexate. However, these are drugs having neither structural similarity to the above-mentioned compounds nor κ opioid receptor agonist activity.
Further, since opioids are known to cause the contraction of the sphincter of Oddi and may, therefore, exacerbate biliary tract diseases, it is known that use of opioids for patients suffering from biliary tract diseases requires caution. Opioids have been reported as follows.
It is described that since morphine, which has a morphinan skeleton similarly to the compounds mentioned above, but is different from those compounds in view of the fact that it is a μ opioid receptor agonist, may cause biliary tract spasm in patients suffering from a gallbladder disorder or cholelithiasis, it needs to be carefully administered to these patients (JAPIC ethical drugs in Japan 2010, edited and published by Japan Pharmaceutical Information Center, available from Maruzen Co., Ltd., p. 2705, Morphine hydrochloride hydrate).
Further, it is described that since oxycodone, which is a μ opioid receptor agonist having a morphinan skeleton, may cause contraction of sphincter of Oddi and, therefore, exacerbate symptoms in patients suffering from a gallbladder disorder, cholelithiasis or pancreatitis, it needs to be carefully administered to these patients (JAPIC ethical drugs in Japan 2010, edited and published by Japan Pharmaceutical Information Center, available from Maruzen Co., Ltd., p. 618, Oxycodone hydrochloride hydrate). Similarly, it is described that since buprenorphine, which is a μ opioid receptor partial agonist having a morphinan skeleton, causes contraction of sphincter of Oddi in animal experiments (with dogs) at high doses (at not less than 0.1 mg/kg i.v.), it needs to be carefully administered to patients suffering from a biliary tract disease (JAPIC ethical drugs in Japan 2010, edited and published by Japan Pharmaceutical Information Center, available from Maruzen Co., Ltd., p. 2166, Buprenorphine hydrochloride). Further, it is described that since tramadol, which is a μ opioid receptor agonist having no morphinan skeleton, causes contraction of sphincter of Oddi in animal experiments at high doses, it needs to be carefully administered to patients suffering from a biliary tract disease (JAPIC ethical drugs in Japan 2010, edited and published by Japan Pharmaceutical Information Center, available from Maruzen Co., Ltd., p. 1713, Tramadol hydrochloride). Similarly, it is described that since pentazocine, which is a μ opioid receptor partial agonist having no morphinan skeleton, may cause contraction of sphincter of Oddi at high doses, it needs to be carefully administered to patients suffering from a biliary tract disease (JAPIC ethical drugs in Japan 2010, edited and published by Japan Pharmaceutical Information Center, available from Maruzen Co., Ltd., p. 2448, Pentazocine).
It is described that κ opioid receptor agonists having no morphinan skeleton are useful as therapeutic agents for gastrointestinal dysfunction, and examples of the gastrointestinal dysfunction include contraction of sphincter of Oddi (WO 05/004796, WO 05/049564, WO 05/023799 and WO 04/093796). However, there is no description on inhibition of contraction of sphincter of Oddi.
Further, in terms of nalbuphine, which is known to have a morphinan skeleton and to have a κ opioid receptor agonist activity and a μ opioid receptor partial agonist activity, there are a report suggesting that it does not exert any action on contraction of sphincter of Oddi (Isenhower H L et al., Am J Health-Syst Pharm., 55, 480 (1998)) and a report showing that it increases the inner pressure of biliary tract by 6% although the action is not statistically significant (Thompson D R., Am J Gastroenterol., 96, 1266 (2001)). However, there is no report suggesting that nalbuphine inhibits contraction of sphincter of Oddi. Further, since butorphanol, which is classified into a κ opioid receptor agonist, increased the inner pressure of biliary tract by 12% and this action was statistically significant (Thompson D R., Am J Gastroenterol., 96, 1266 (2001)), it has been shown to have contraction of sphincter of Oddi. Further, it is described that since eptazocine, which is known to have no morphinan skeleton but act as a κ agonist on opioid receptors, shows an action to cause contraction of sphincter of Oddi at high doses in animal experiments, it needs to be carefully administered to patients suffering from a biliary tract disease (JAPIC ethical drugs in Japan 2010, edited and published by Japan Pharmaceutical Information Center, available from Maruzen Co., Ltd., p. 549, Eptazocine hydrobromate).
Leucine enkephalin and methionine enkephalin, which are endogenous δ opioid receptor agonist peptides, are reported to cause transient contraction of sphincter of Oddi, followed by showing a continuous contraction inhibition action (Behar J et al., Gastroenterol., 86, 134 (1984)). Further, naloxone, which is a μ opioid receptor antagonist having a morphinan skeleton, is also known to have an action to inhibit contraction of sphincter of Oddi (Behar J et al., Motiltiy of the Digestive Tract, New York: Raven, (1982), p. 397).
Thus, no suggestion has been made at all on inhibition of contraction of sphincter of Oddi by opioid κ receptor agonists having a morphinan skeleton similar to the above-mentioned compounds.
It has been disclosed that the compounds mentioned above show antagonistic actions on the ORL-1 receptor. Since nociceptin (which is sometimes referred to as “orphanin FQ”), which is an endogenous agonist peptide of this receptor, is expressed in the excitatory motor neurons in the myenteric plexus of sphincter of Oddi and inhibits cholinergic neurotransmission, it has been suggested that nociceptin may act on sphincter of Oddi via a feedback autoinhibitory mechanism (O'Donnell A M et al., J Comp Neurol., 29, 430 (2001)).
Thus, ORL-1 receptor agonists are believed to inhibit contraction of sphincter of Oddi, but inhibition of contraction of sphincter of Oddi by an antagonistic action on the ORL-1 receptor has not been suggested.
It could therefore be helpful to provide a therapeutic or prophylactic agent for a biliary tract disease(s) having an excellent effect, which agent comprises as an effective component a specific compound having a morphinan skeleton or a pharmaceutically acceptable acid addition salt thereof.